Activation of peripheral opioid receptors inhibits pain in inflammation. We examined the contribution of opioid receptors on sympathetic postganglionic neurons (SPN) versus primary afferent neurons (PAN) to peripheral opioid analgesia. In rats with hindpaw inflammation, the local (intraplantar) injection of mu-, _- and k-opioid agonists produced dose- dependent analgesic effects. Pretreatment with capsaicin attenuated these effects to a much higher degree than pretreatment with 6-hydroxydopamine, suggesting that opioid receptors are present on PAN and SPN, but that the former contribute to a greater extent to peripheral opioid analgesia than the latter. Opioid peptides are synthesized within resident immune cells of the inflamed tissue. After being released they also activate peripheral opioid receptors as endogenous ligands, and produce similar analgesic effects. We investigated opioid production and release from immune cells in vitro. POMC mRNA levels were higher in immune cells of inflamed versus noninflamed popliteal lymph nodes (LN), whereas the beta- endorphin content was lower, suggesting that immune cells have released most of their beta-endorphin when they return from the inflamed paw to the draining LN. Stimulation of immune cells with corticotrophin- releasing factor (CRF) and interleukin-1 (IL-1) triggers release of beta- endorphin in a receptor specific and calcium dependent manner. Intraplantar injection of CRF and IL-1 produces potent analgesic effects in vivo mediated by a release of opioid peptides from immune cells. Inhibition of CRF synthesis in inflamed tissue with a CRF antisense oligodeoxynucleotide abolishes endogenous local opioid analgesia. These findings demonstrate that the immune system plays an important role in pain control. This has wide ranging implications for the understanding of the pathophysiology of pain in immunosuppressed conditions such as AIDS. In addition, these studies provide an incentive for the development of novel compounds that either target peripheral opioid receptors exclusively (prototypes have been developed by several pharmaceutical companies), or that trigger a release of local endogenous opioid peptides from immune cells, a prototype of which would be CRF. The advantage of such a peripheral approach for the treatment of pain is the lack of central opioid side effects such as euphoria, addiction or dependence. This may lead to a reduction of the use and availability of conventional centrally acting opioids and, thus, reduce the prevalence of opioid abuse and ensuing problems such as AIDS.